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Updated: Jan 3, 2026
Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
Published on: August 11, 2017
Distinct co-acquired alterations and genomic evolution during TKI treatment in non-small-cell lung cancer patients
Ying Jin1,2,3, Hua Bao4, Xiuning Le5
1Institute of Cancer and Basic Medicine, Chinese Academy of Sciences, Hangzhou, Zhejiang, China.
Abstract:
EGFR-mutant non-small-cell lung cancer (NSCLC) patients inevitably develop drug resistance when treated with EGFR tyrosine kinase inhibitors (TKIs). Systematic genetic analysis is important to understand drug-resistant mechanisms; however, the clinical significance of co-occurring genetic alterations at baseline, co-acquired mutations at progressive disease (PD), and the clonal evolution remain underinvestigated. We performed targeted sequencing of pre-treatment and PD tumor samples from 54 EGFR-mutant NSCLC patients. Ten additional patients were sequenced using whole-exome sequencing to infer the clonal evolution patterns. We observed a domain-dependent effect of PIK3CA mutation at baseline on patient progression-free survival (PFS). In addition, at baseline, 9q34.3/19p13.3 (NOTCH1/STK11/GNA11) showed a co-deletion pattern, which was associated with a significantly worse PFS (p = 0.00079). T790M-postive patients with other concurrent acquired oncogenic mutations had a significantly shorter PFS (p = 0.005). Besides acquired T790M mutation, chromosomal instability (CIN) related genes, including AURKA and TP53 alterations, were the most frequently acquired events. CIN significantly increased during TKI treatment in T790M-negative patients and is a candidate resistance mechanism to the first-generation TKIs. Clonal evolution analyses suggest that the composition and relationship among resistant subclones, particularly relationship with T790M subclone, affect patients' outcomes. Overall, our findings of novel co-occurring alterations and clonal evolution patterns can be served as predictive biomarkers to stratify patients and help to better understand the drug-resistant mechanism to TKIs.
Insights
Understanding EGFR-mutant non-small-cell lung cancer (NSCLC) drug resistance requires analyzing genetic changes. New co-occurring mutations and chromosomal instability (CIN) offer insights into resistance mechanisms and potential biomarkers.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- EGFR-mutant non-small-cell lung cancer (NSCLC) patients often develop resistance to EGFR tyrosine kinase inhibitors (TKIs).
- Mechanisms of drug resistance, including baseline genetic alterations, acquired mutations, and clonal evolution, are not fully understood.
- Identifying these mechanisms is crucial for improving treatment strategies.
Purpose of the Study:
- To investigate the clinical significance of co-occurring genetic alterations at baseline and acquired mutations at progressive disease (PD) in EGFR-mutant NSCLC patients treated with TKIs.
- To explore clonal evolution patterns and their impact on treatment resistance.
- To identify potential predictive biomarkers for TKI resistance.
Main Methods:
- Targeted sequencing of pre-treatment and PD tumor samples from 54 EGFR-mutant NSCLC patients.
- Whole-exome sequencing of 10 additional patients to infer clonal evolution.
- Statistical analysis to correlate genetic alterations with progression-free survival (PFS).
Main Results:
- A domain-dependent effect of PIK3CA mutation at baseline on PFS was observed.
- Co-deletion of 9q34.3/19p13.3 (NOTCH1/STK11/GNA11) at baseline was associated with significantly worse PFS.
- Acquired T790M mutation with concurrent oncogenic mutations correlated with shorter PFS.
- Chromosomal instability (CIN) related genes (AURKA, TP53) were frequently acquired, and CIN increased during TKI treatment in T790M-negative patients.
- Clonal evolution analysis indicated that the composition and relationships of resistant subclones impact patient outcomes.
Conclusions:
- Novel co-occurring genetic alterations at baseline and acquired mutations contribute to TKI resistance in EGFR-mutant NSCLC.
- Chromosomal instability (CIN) is a potential resistance mechanism, particularly in T790M-negative patients.
- Understanding clonal evolution and genetic alterations can aid in stratifying patients and developing targeted therapies.
